Tocilizumab was a drug used to treat rheumatoid arthritis. But, during the Covid-19 pandemic it was used as an injection to treat the symptoms of the coronavirus. The pandemic led to many drugs being repurposed. Examples include hydroxychloroquine, HIV drugs and vitamin C.
The drug developed by Gilead for Ebola received FDA approval for emergency use for Covid-19 patients. Subsequently, India, too, gave approval for emergency use. Favipiravir, a drug used to treat new strains of influenza, received emergency use authorisation from the FDA and in India for mild to moderate Covid-19 patients.
Then, in 2021, the UK's National Health Services started a project called Medicines Repurposing Programme. Its aim is finding alternative use for existing medicines.
But, perhaps the project was not so novel. Experts say that this has been going on for centuries. Many a time, drugs have been repurposed without being labelled so. The oldest example of drug repurposing is aspirin, and it is also the drug that has been repurposed the most.
When German company Bayer discovered the molecule in 1899, it was thought of as an analgesic. Later, it was found that aspirin also helped in decreasing blood clots. As a result, it was approved for use as an antiplatelet drug and millions across the world used low doses of aspirin to prevent heart attacks. This discovery came almost a century after aspirin was discovered and it led to a Nobel Prize. Now, research has it that aspirin may help in the prevention of colon cancer.
Similarly, sildenafil (better known as Viagra), developed by US pharmaceutical company Pfizer in 1989, was a drug to lower blood pressure. But, during trials, people gave feedback that they were getting penile erections. So, it was marketed as a drug to treat erectile dysfunction. Later, as the drug was also helping in dilatation of the blood vessels, it began to be used for a more serious illness called pulmonary artery hypertension.
“This is a much easier and quicker way of getting a new drug into the market rather than spending billions of dollars on discovering a new molecule and going through the testing stages and checking the safety and efficacy,” says Dr Monica Mahajan, director, internal medicine, Max Healthcare.
Over time, a high number of repurposed drugs have been used in the treatment of different pathologies through the strategic redirection of existing molecules or compounds that have already passed safety tests. In fact, AI and machine learning play a huge role in this, say experts. As per a paper published in Nature, titled, 'Drug repurposing: A nexus of innovation, science, and potential', these computational methods allow researchers to sift through vast amounts of data, identify hidden patterns, and generate insights that would be difficult to uncover through traditional means.
Propranolol (brand name Ciplar-LA) was initially meant to be used for managing high blood pressure and is now used for anxiety, palpitation and as a prophylactic for migraines. It is a beta blocker, which means it works by changing the way the body responds to some nerve impulses, including in the heart. It slows down your heart rate and makes it easier for your heart to pump blood around your body. It is worth mentioning that propranolol was also registered in a clinical trial with paediatric patients affected by recurrent respiratory papillomatosis with positive results.
Dr Mohit Sharma, senior consultant, internal medicine, Amrita Hospital, Faridabad, says there are medicines that are more successful in their repurposed avatar. “SGLT2 inhibitors, namely dapagliflozin, empagliflozin and canagliflozin, were initially made to control glucose levels in diabetics by making the person excrete sugar in the urine, but now they have been found to be beneficial in improving morbidity and mortality in patients with heart failure and early chronic kidney disease,” he says. “So, it has found two more uses for which it is used more than for diabetes. It was not that successful as an anti-diabetic medicine. It is a recent drug and for us practising physicians it is a revolutionary medicine. Because research shows that it improves the lifespan and prognosis and reduces mortality rate in patients with heart failure.”
He adds that glipizide is an “emerging repurposed drug”. A diabetes medicine used commonly in the US, it can be effectively repurposed for treatment of some devastating human brain disorders such as Huntington’s disease and other polyQ disorders, according to researchers at Delhi University’s genetics department. In the UK and in India, other salts from the same family, like gliclazide and glimepiride, are more common. And as glipizide is found to have a repurposed role, there might soon be research into other drugs of the same class.
So, what is the process for deciding which medicines can be repurposed and for what? “The repurposing of medicines has been done regularly whenever there is an infection or any kind of disease which is either not responding to other medication or is not identified in detail,” says Dr Abdul Samad Ansari, director, critical care services, Nanavati Max Super Specialty Hospital. “Two things which are simultaneously done are identification of the causation and the mechanism of the illness, whether it is an infectious or non-infectious disease, how the disease progresses.”
He cites the example of psoriasis. “That is one ailment and the other is Covid-19 and the scientist and the physician try to find the similarities between the pathogens, the etymology and then pharmaceutical research collaborates with biological research to understand the type of virus and pathogen, the type of disease, and look at the whole compendium of drugs which fit the bill,” he says. “The point is to look backwards. For example, For Covid-19, the WHO listed hundreds of drugs which had potential. They looked in the past for RNA viruses as Covid-19 was also [caused by] an RNA virus.”
The key step, he says, is to apply the syndromic approach. “That is classifying the disease into syndromes to figure out easily identifiable group of symptoms and signs and most common organisms causing the syndrome,” he says “So, for instance, in polio, upon observing the symptoms, you immediately draw out a parallel with acute flaccid paralytic conditions and then look backwards to see the data in similar conditions to map the disease trajectory and then repurpose the drug for that broad group in which the disease is. This is how hydroxychloroquine, tocilizumab and remdesivir were found and used in the treatment of Covid-19.”
Dr Monica Mahajan
Sharma gives an example of how a drug can treat two interrelated conditions simultaneously. GLP1 receptor agonists were used for glucose control in diabetes, but is now used to cause weight loss in morbidly obese patients. “This way we now have a dual action for diabetic patients who are also overweight,” he says.
Scientist and computational biologist Rituraj Purohit, who works on ayurvedic medicines and contributed to the aforementioned paper in Nature, tells THE WEEK about Himalayan bioactive molecules he works on. He examines how they could be used for treating illnesses other than those they have been traditionally used for. “We repurposed turmeric―two important molecules from turmeric can directly inhibit or demolish viral activity,” he says. “Likewise, we also reported molecules from fennel seeds that could be used against Covid-19.
“Recently, we repurposed molecules from a Himalayan herb called Thalictrum foliolosum for the treatment of cancer and MDR TB. Earlier it was used for anti-bacterial activity. “We started this work two years ago, after the prime minister said we have to find solutions to eliminate TB from India,” he says. “We screened herbs which are used against bedaquiline-resistant TB and that is how we came across the molecule of Thalictrum foliolosum.”
Mahajan of Max Healthcare points out the drug thalidomide. “It became notorious because it was used in women during pregnancy to prevent vomiting, but resulted in babies being born with deformed arms,” she says. “This drug was then banned. Later on, it was found that it was a good drug for the complications of leprosy. And then, it was found that it was also a wonderful drug to fight the cancer multiple myeloma.”
Rituraj Purohit
Many older drugs have been repositioned for the treatment of Alzheimer's. “There is a drug called pioglitazone, used to treat type-2 diabetes,” says Mahajan. “But now there is data to suggest that this drug may have a role in the treatment of Alzheimer's. The combination of pioglitazone and insulin, as per research, may have a potentially positive effect on decreasing the risk of developing Alzheimer's.”
Multiple sclerosis, an autoimmune disease which affects the central nervous system, is another area where drugs have been repositioned. An academic paper in the journal Frontiers in Neurology says dimethyl fumarate is an effective treatment option for multiple sclerosis. Dimethyl fumarate was originally used in the treatment of psoriasis, a skin disease.
The recent licensing of anastrozole by the Medicines and Healthcare products Regulatory Agency in the UK, for preventive use marks a milestone. The drug was previously used for breast cancer treatment. Recent trials have shown that it can reduce the incidence of the disease in post-menopausal women at increased risk by almost 50 per cent.
Another example where drugs have been repositioned to treat neglected diseases is the case of leishmaniasis, a parasitic disease classified as a neglected tropical disease. It is caused by leishmania parasites, which are spread by the bite of sandflies. Two repurposed drugs are being used to treat this―amphotericin B, an anti-fungal, and miltefosine, an anti cancer drug.
Dr Abdul Samad Ansari
Repurposed drugs are especially effective in the treatment of rare diseases. In such cases, since the affected population is low, it is not commercially sustainable for pharma companies to create specific treatments. According to a report by the ministry of health and family affairs, aroun 96 million people in India are affected by some kind of rare disease, with limited options for treatment. As per a study by Khujith Rajueni from the department of clinical pharmacy, Poona College of Pharmacy, Bharati Vidyapeeth University, Pune, India’s patent regime prevents the evergreening of drugs and a large generic manufacturing industry provides ample opportunity to explore the potential of repurposed orphan drugs for treating rare diseases.